EA016419B1

EA016419B1 - Method for the preparation of 5-benzyloxy-2-(4-benzyloxphenyl)-3-methyl-1h-indole

Info

Publication number: EA016419B1
Application number: EA200901088A
Authority: EA
Inventors: Йосеф Ирман; Индрих Рихтер
Original assignee: Зентива, К.С.
Priority date: 2007-02-12
Filing date: 2008-02-11
Publication date: 2012-04-30
Also published as: CZ2007110A3; EA200901088A1; US20100087661A1; EP2118058B1; EP2118058B9; ATE512134T1; WO2008098527A1; UA99725C2; CZ302094B6; PL2118058T3; EP2118058A1

Abstract

A method for the preparation of 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1H-indole of formula (1) by reaction of 2-bromo-4'-benzyloxypropiophenone and 4-benzyloxyaniline hydrochloride, in which high purity of the product is achieved by isolation of the intermediate, N-(4-benzyloxyphenyl)-a-amino-4-benzyloxypropiophenone of formula (10), in the solid state. The method may be used for the preparation of bazedoxifen of formula (2).

Description

The invention relates to a new method for producing 5-benzyloxy-2- (4-benzyloxyphenyl) -3-methyl1H-indole of formula (1)

. (P used to obtain 2- (4-hydroxyphenyl) -1- [4- (2-azepan-1-methoxy) benzyl] -3-methyl-1H-indole 5-ol (bazedoxifene) of the formula (2)

(2)

Bazedoxifen is an estrogen agonist; It is used in hormone replacement therapy to prevent bone loss, replace estrogen, and prevent heart and vein disease in postmenopausal women.

Prior art

Two similar methods are known from the literature for producing bazidoxifene — see Scheme 1. These methods differ in protecting groups (PO — methyl, benzyl), the method of producing and binding the chain to nitrogen in the indole heterocycle, and the method of removing the protecting group.

5-Methoxy-2- (4-methoxyphenyl) -3-methyl-1H-indole of formula (3a) was obtained by the Bisher method (1.Meb. SBech. 1984, 27, 1439-1447; \\ O 9603375) from 2-bromo -4'-methoxypropiophenone of formula (5) and paraanisidine of formula (6) in ortho-xylene in the presence of Ν, Ν-dimethylaniline. 2-Bromo-4'methoxypropiophenone of formula (5) is obtained by brominating 4-methoxypropiophenone of formula (4) with bromine in acetic acid (\\ O 9603375), see scheme 2.

Scheme 2

The total yield of the two-stage synthesis is 22%.

5-Benzyloxy-2- (4-benzyloxyphenyl) -3-methyl-1H-indole of formula (1) was also prepared by the Bisher method from 2-bromo-4'-benzyloxypropiophenone of formula (8) and 4-benzyloxyaniline hydrochloride of formula (9) in Ν,-dimethylformamide (EP 0802183). 2-Bromo-4'-benzyloxypropiophenone of formula (8) is prepared by brominating 4-benzyloxypropiophenone of formula (7) with bromine in acetic acid. The overall yield of the two-stage synthesis (see Scheme 3) is 47%.

B \ O 99/19293 mentions the implementation of the second stage in toluene by boiling with reverse cold with a Ν, ди-diisopropylethylamine, but without any further details in the examples or literary references.

Testing syntheses showed that the use of the above methods does not allow to obtain the compounds of formula (1) with a sufficiently high yield and especially with sufficient purity.

When reproducing the method according to patent EP 802183 (Scheme 4), it was found that during this synthesis significant amounts of undesirable substances are formed.

Isolation of the compound of formula (1) obtained by this method is considerably difficult, and when it is purified, the yield is significantly reduced.

When carrying out the reaction in accordance with patent application G) 99/19293, which describes the preparation of a compound of formula (1) in toluene and Ν,-diisopropylethylamine with simultaneous removal of water by azeotropic distillation, it was found that the reaction takes several tens of hours . During this time, a significant amount of secondary substances is already formed, which reduces the yield and impairs the quality of the product.

For this reason, an attempt was made to find a more efficient way of synthesis, which resulted in a new method for producing 5-benzyloxy-2- (4-benzyloxyphenyl) -3-methyl-1H-indole of formula 1, which is the subject of the present invention.

Description of the invention

The invention relates to a new method for producing 5-benzyloxy-2- (4-benzyloxyphenyl) -3-methyl1H-indole of formula 1, which is based on the isolation of intermediate N- (4benzyloxyphenyl) -a-amino-4-benzyloxypropiophenone of formula (10). This intermediate is preferably obtained by reacting 4-benzyloxyaniline or its salt with the compound of the formula (11)

(11) where bC is a leaving group, for example, C1, Br, I, alkylsulfonyl, or arylsulfonyl.

The method of obtaining includes:

a) the reaction of 2-bromo-4'-benzyloxypropiophenone of formula (8) with para-benzyloxyaniline hydrochloride of formula (9), and the reaction is carried out in the medium of an organic solvent from the group C ₁ -C ₄ alcohols, toluene, acetone, methyltetrahydrofuran and in the presence of inorganic or an organic base from the group consisting of sodium carbonate, potassium carbonate, diisopropylethylamine (DIPEA) and triethylamine;

Scheme 5

GP

(ten)

b) isolating the No. (4-benzyloxyphenyl) -a-amino-4-benzyloxypropiophenone of formula (10) in the solid state;

c) cyclization of the No. (4-benzyloxyphenyl) -a-amino-4-benzyloxypropiophenone of formula (10) by reaction with para-benzyloxyaniline hydrochloride of formula (9) in the medium of a suitable organic solvent from the group C ₁ -C ₄ alcohols, toluene, acetone, methyltetrahydrofuran to obtain 5-benzyloxy-2 (4-benzyloxyphenyl) -3-methyl-1H-indole of formula (1) in the solid phase.

It was found to be advantageous to carry out the synthesis of 5-benzyloxy-2- (4-benzyloxyphenyl) -3-methyl-1 Nindole of formula (1) in two stages with isolation of the intermediate compound of formula (10) in accordance with Scheme 7.

In the first stage, the starting compounds (8) and (9) react in the medium of an organic solvent from the group of C1-C4 alcohols, toluene, ketones, methyltetrahydrofuran, preferably ethanol, and an inorganic or organic base from the group comprising sodium carbonate, triethylamine and DIPEA, preferably triethylamine, at boiling point for 4-6 hours. Under these conditions, after a few hours, a suspension of intermediate 10 and possibly inorganic salts (corresponding to the base used) is formed. The intermediate is isolated by filtration. The product yield ranges from 81 to 100%.

The product can be recrystallized by dissolving in a mixture of polar and non-polar solvent (ethyl acetate-ethanol, toluene-methanol, THF (tetrahydrofuran) methanol).

In the second stage, X- (4-benzyloxyphenyl) -a-amino-4-benzyloxypropiophenone of formula (10) is suspended together with para-benzyloxyaniline hydrochloride of formula (9) (molar ratio 1: 201: 1, preferably 1: 5 with respect to the compound formula (10)) in an organic solvent from the group of C1-C4 alcohols, toluene and methyltetrahydrofuran, preferably ethanol, and the mixture is heated in an autoclave in an inert atmosphere at 100-120 ° C. After a few hours (4-5), the reaction mixture is cooled to room temperature. The crystallized product, 5-benzyloxy-2- (4-benzyloxyphenyl) -3methyl-1H-indole of formula (1), is filtered off, washed with ethanol and possibly recrystallized from a mixture of a polar and non-polar solvent (ethyl acetate-ethanol, toluene-methanol, THF methanol). The reaction yield ranges from 75 to 80%.

Advantageously, the starting aniline of formula (9) can be obtained from the mother liquor, after concentrating and stirring the concentrated mixture in ethyl acetate, again in almost 100% yield.

This original method is based on the production and isolation of a new substance, the intermediate compound X- (4-benzyloxyphenyl) -a-amino-4-benzyloxypropiophenone of formula (10). The main advantages of this method are higher yield (60-75%) as compared with the known methods (35-53%), simple isolation of intermediate X- (4-benzyloxyphenyl) -a-amino4-benzyloxypropiophenone of formula (10), and also the final product 5-benzyloxy-2- (4benzyloxyphenyl) -3-methyl-1H-indole of formula (1) by filtering directly from the reaction mixture without using any additional chemicals and, moreover, achieving high quality in the crude product ( 98-100% according to HPLC). Another advantage is that the initial benzyloxyaniline hydrochloride of formula (9) used in the cyclization reaction is not consumed and can be obtained from the stock solutions after separation of 5-benzyloxy-2- (4-benzyloxyphenyl) -3 methyl-1H-indole of formula (1 ) with a quantitative yield.

Brief description of graphic materials

The drawing is a picture of X- (4-benzyloxyphenyl) -a-amino-4-benzyloxypropiophenone X-ray diffractometry of formula (10) (X-ray analysis conditions: analytical X-ReP diffractometer, CuKa radiation (1 = 1.542 A) in the range of 4-40 ° 2 with an increase of 0.008.

Examples

The invention is described in more detail by the following examples.

Preparation of X- (4-benzyloxyphenyl) -a-amino-4-benzyloxypropiophenone (10).

1) a-Bromo-4-benzyloxypropiophenone (20 g; 62.7 mmol), 4-benzyloxyaniline (16 g; 67.9 mmol) and triethylamine (19 ml; 136.4 mmol) were suspended in 250 ml of toluene and the mixture was boiled under reflux for 5 hours. Then the reaction mixture was filtered and concentrated to approximately 1/3 of the volume. Ethanol (80 ml) was added to the concentrated mixture and the mixture was cooled to 5 ° C. After filtration, 19.2 g (71%) of gray product, X- (4-benzyloxyphenyl) -a-amino-4 was obtained

- 3 016419 benzyloxypropiophenone (10), with a melting point of 124.5-126 ° C.

2) a-Bromo-4-benzyloxypropiophenone (26 g; 81.5 mmol), 4-benzyloxyaniline (23 g; 97.8 mmol) and sodium carbonate (20.7 g; 196 mmol) were suspended in 300 ml of ethanol and the mixture boil under reflux for 5 hours. The product precipitates during the indicated time. After cooling the reaction mixture, a mixture of salts (NaBr, NaC1, sodium carbonate) and crystallized product were isolated by filtration. The selected mixture of substances was dissolved in a mixture of toluene-water. After separation of the aqueous phase, the organic phase was concentrated. Ethanol was added to the concentrated residue. The precipitated slightly yellow crystalline product was separated by filtration and washed with ethanol. 30.2 g (85%) of L- (4-benzyloxyphenyl) -a-amino-4-benzyloxypropiophenone (10) were obtained. Melting point 126,0127,1 ° C.

3) a-Bromo-4-benzyloxypropiophenone (16.1 g; 50.5 mmol), 4-benzyloxyaniline (14.2 g; 60.1 mmol) and triethylamine (16.1 ml; 115.6 mmol) were suspended in 130 ml of ethanol and the mixture was boiled under reflux for 5 hours. Then, with stirring, the mixture was cooled for 1 hour to room temperature. The filtered product was washed with ethanol and dried. 21.9 g (99.5%) of N- (4benzyloxyphenyl) -a-amino-4-benzyloxypropiophenone (10) were obtained. Melting point 122.6-125.4 ° C.

The crude product, No. (4-benzyloxyphenyl) -a-amino-4-benzyloxypropiophenone (10) (15.4 g) was dissolved in toluene (40 ml) by heating to 60 ° C. The solution was filtered and ethanol (40 ml) was added to the filtrate. After cooling to 10-15 ° C, 13.8 g (89.6%) of a white product was obtained with a melting point of 126.1-127.1 ° C.

¹ H-NMR (DMSO) δ 8.10 (ά, 2H); 7.3-7.5 (t, 12H); 7.19 (, 2H); 7.06 (ά, 2H); 5.5 (, 1H); 5.24 (8, 2H); 5.08 (8, 2H); 1.48 (ά, 3H).

X-ray diffraction pattern of the obtained product is shown in the drawing; characteristic diffraction angles of 2Θ: 6.71; 19.00, 19.13; 23.49; 23.63.

Preparation of 5-benzyloxy-2- (4-benzyloxyphenyl) -3-methyl-1 H-indole (1).

1) Source No. (4-benzyloxyphenyl) -a-amino-4-benzyloxypropiophenone (22) (30.4 g; 69.7 mmol) and 4-benzyloxyaniline hydrochloride (3.3 g; 13.9 mmol) were suspended in ethanol (380 ml) and the mixture was heated to 110-115 ° C in an inert atmosphere in an autoclave. After 5 h, the heating was stopped and the reaction mixture was stirred overnight. The white crystalline product was filtered and washed with ethanol. 23.3 g (79%) of 5-benzyloxy-2- (4-benzyloxyphenyl) -3-methyl-1H-indole (3b) were obtained with a melting point of 152.4-153.4 ° C.

¹ H-NMR (DMSO) δ 10.65 (8, 1H); 7.55 (ά, 2H); 7.50 (, 4H); 7.30-7.45 (t, 6H); 7.21 (ά, 1H); 7.10 (ά, 2H); 7.10 (ά, 1H); 6.91 (άά, 1H); 5.16 (8, 2H); 5.11 (8, 2H); 2.33 (8, 3H).

MS eu (mass spectrometry, electron impact) t / ζ 419.

2) Original No. (4-benzyloxyphenyl) -a-amino-4-benzyloxypropiophenone (22) (30.4 g; 69.7 mmol) and 4-benzyloxyaniline hydrochloride (3.3 g; 13.9 mmol) were suspended in propane -2-Ole (380 ml) and the mixture was heated to 110-115 ° C in an inert atmosphere in an autoclave. After 5 h, the heating was stopped and the reaction mixture was stirred overnight. The beige crystallized product was filtered and washed with a small amount of propan-2-ol. 24.2 g (82%) of 5-benzyloxy-2- (4-benzyloxyphenyl) 3-methyl-1H-indole (3b) with a melting point of 152.0-153.2 ° C were obtained.

The mother liquors after filtration were concentrated and the concentrate was stirred in ethyl acetate (30 ml). The precipitate of crystalline substance was filtered. 3.3 g of 4-benzyloxyaniline hydrochloride hydrochloride were obtained.

Claims

CLAIM

1. The method of obtaining 5-benzyloxy-2- (4-benzyloxyphenyl) -3-methyl-1H-indole of the formula (1) n

0) characterized in that it includes:

a) the reaction of 2-bromo-4'-benzyloxypropiophenone of the formula (8) with para-benzyloxyaniline hydrochloride of the formula (9)

- 4 016419 in an environment of an organic solvent and in the presence of an inorganic or organic base;

b) isolation of intermediate compound No. (4-benzyloxyphenyl) -a-amino-4benzyloxypropiophenone of the formula (10) in the solid state;

c) preparation of 5-benzyloxy-2- (4-benzyloxyphenyl) -3-methyl-1H-indole of formula (1) by cyclization of Ν (4-benzyloxyphenyl) -a-amino-4-benzyloxypropiophenone of formula (10) by the action of parabenzyloxyaniline hydrochloride of the formula ( 9) in an environment of an organic solvent from the group of alcohols C ₁ -C ₄ , toluene, acetone and methyltetrahydrofuran

2. The method according to claim 1, characterized in that the reaction is carried out in an organic solvent from a group of C1-C4 alcohols, toluene, acetone, methyl tetrahydrofuran and in the presence of an inorganic or organic base from a group comprising sodium carbonate, potassium carbonate, triethylamine, diisopropylethylamine .

3. The method according to claim 2, characterized in that ethanol is used as a solvent, and triethylamine is used as a base.

4. The method according to any one of claims 1, 2, characterized in that the reaction is carried out at the boil under reflux.

5. The method according to any one of claims 1 to 4, characterized in that the intermediate N- (4benzyloxyphenyl) -a-amino-4-benzyloxypropiophenone is further purified by crystallization from an organic solvent that is selected from the group of liquid C ₁ -C ₁₅ aliphatic, alicyclic or aromatic hydrocarbons or their oxidized or nitrogen-containing derivatives or mixtures thereof.

6. The method according to claim 5, characterized in that a mixture of a polar and non-polar solvent, such as a mixture of ethyl acetate-ethanol, toluene-methanol, THF (tetrahydrofuran) -methanol, is used to crystallize the intermediate.

7. The method according to claim 1, characterized in that the para-benzyloxyaniline hydrochloride of formula (9) is used in a molar ratio of from 1:20 to 1: 1, preferably 1: 5 with respect to the compound of formula (10).

8. The method according to claim 1 or 7, characterized in that the reaction is carried out in an autoclave in an inert atmosphere at an elevated temperature of 100-120 ° C.

9. The method according to claims 1, 7 or 8, characterized in that an organic solvent from the group of C ₁ -C ₄ alcohols is used, preferably ethanol.

10. Crystalline No. (4-benzyloxyphenyl) -a-amino-4-benzyloxypropiophenone of the formula (10).

11. The substance according to claim 10, characterized in that it has the following values of the characteristic diffraction angles 2Θ on the profile of powder x-ray diffractometry: 6.71; 19.00; 19.13; 23.49; 23.63.

12. The use of No. (4-benzyloxyphenyl) -a-amino-4-benzyloxypropiophenone of the formula (10) for the preparation of 5-benzyloxy-2- (4-benzyloxyphenyl) -3-methyl-1H-indole of the formula (1).

13. The use of No. (4-benzyloxyphenyl) -a-amino-4-benzyloxypropiophenone of the formula (10) for the preparation of 2- (4-hydroxyphenyl) -1- [4- (2-azepan-1-ylethoxy) benzyl] -3- methyl-1H-indol-5-ol (bazedoxifene) of the formula (2).